Alzheimer's Disease

In a healthy adult brain, there are about 100 billion neurons, each forming connections with other neurons through long, branching extensions. Alzheimer’s disease (AD) is defined neuropathologically by two neuronal lesions: intracellular protein tau aggregates of an abnormal form of the microtubule-associated called tau or neurofibrillary tangles and neuritic plaques composed of focally swollen (dystrophic) neurites (DNs), extracellular β-amyloid and many other proteins in clusters called beta-amyloid plaques. Additionally, in yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) containing incompletely digested autophagy substrates accumulate progressively packed into large membrane blebs forming flower-like perikaryal rosettes within affected neurons at the earliest disease stage and promoting senile amyloid plaques. The presence of plaques and tangles of these toxic proteins leads to thermogenic dysfunction, progressive failure of autophagy response, neuronal cell death involving lysosomal membrane permeabilization, mitochondrial degradation, cathepsin release, and, ultimately, glial invasion and extracellular plaque expansion, activation of the immune system, resulting in chronic inflammation and atrophy due to cell loss. Brain function is further compromised in Alzheimer’s disease by the brain’s decreased ability to metabolize glucose, its primary fuel, and the dysregulation of the excitatory glutamatergic transmission and synaptic failure.